Over the past few years, we completed human trials of recombinant glycoprotein vaccines for treatment and prevention of genital herpes. The vaccines proved inadequate. We turned, therefore, to animal model studies using new classes of HSV vaccines to define ones that appear to be more immunogenic and potentially more effective. We are testing novel DNA-based and live, genetically-engineered vaccines for genital herpes. This has the theoretical advantage of inducing better CTL responses. Studies in mice and guinea pigs using vectors expressing HSV-2 gD verified that DNA-based vaccines are highly protective against HSV2 infection. The coadministration of vectors for selected HSV regulatory genes did not enhance the activity of gD-expressing vectors. We are also testing a live disabled infectious single cycle HSV2 vaccine deleted for two essential genes, rendering the virus able to infect but not complete its replicative cycle or be transmitted to infect additional cells. In mice and guinea pigs this vaccine induced at least as much protection against primary and recurrent disease as does the recombinant vaccine. Further studies will be quantifying the spewcific components of immune repsonses elicited by each of these candidate vaccines.